The acetylcholine neurotransmitter system plays a significant role in a variety of central nervous system (CNS) and peripheral functions. Acetylcholine signaling occurs through two different families of receptors: nicotinic receptors and muscarinic receptors. Muscarinic cholinergic receptors are G-protein coupled receptors with five different receptor subtypes (M1-M5) (Raedler et al. American Journal of Psychiatry. 160: 118. 2003), each of which are found in the CNS but have different tissue distributions. Activation of the muscarinic system through use of muscarinic agonists has been suggested to have the potential to treat several diseases including Alzheimer's disease, Parkinson's disease, movement disorders and drug addiction. (US 2005/0085463; Langmead et al. Pharmacology & Experimental Therapeutics. 117: 232:2008). Genetic evidence has suggested a direct link between the muscarinic system and both alcohol addiction (Luo X. Et al. Hum Mol Genet. 14:2421. 2005) and nicotine addiction (Mobascher A et al. Am J Med Genet B Neuropsychiatr Genet. 5:684. 2010). M1 and M4 subtypes have been of particular interest as therapeutic targets for various diseases. For instance, the mood stabilizers lithium and valproic acid, which are used to treat bipolar depression, may exert their effects via the muscarinic system particularly through the M4 subtype receptor. (Bymaster & Felder. Mol Psychiatry. 7 Suppl 1:S57. 2002).
Some of the strongest linkages to the muscarinic system have been with schizophrenia, which is a serious mental illness affecting approximately 0.5-1% of the population. (Arehart-Treichel. Psych News. 40:9. 2005). The disease is characterized by a set of symptoms that are generally divided into three categories: 1) Positive symptoms (e.g., hallucinations, delusional thoughts, etc.); 2) Negative symptoms (e.g., social isolation, anhedonia, etc.); and 3) Cognitive symptoms (e.g., inability to process information, poor working memory, etc.). (Schultz. Am Fam Physician. 75:1821. 2007). Patients who suffer from schizophrenia both experience a major decline in quality of life and are at increased risk for mortality due to a number of factors, such as an increased suicide rate. (Brown et al. British Journal of Psychiatry. 177: 212. 2000). The cost of schizophrenia to society is also significant as sufferers of schizophrenia are much more likely to be incarcerated, homeless or unemployed.
Today, antipsychotics are the mainstay of treatment for schizophrenia. The first generation of antipsychotics are generally known as “typical antipsychotics” while newer antipsychotics are generally called “atypical antipsychotics.” Both typical and atypical antipsychotics have limited efficacy and severe side effects. There is little to no difference in efficacy between typical and atypical antipsychotics, most likely due to the fact that both classes of drugs achieve their therapeutic effect through the same pharmacological mechanisms (e.g., acting as dopamine receptor antagonists). (Nikam et al. Curr Opin Investig Drugs. 9:37. 2008). Side effects of typical antipsychotics include abnormal movement (e.g., rigidity) whereas atypicals have different but equally significant side effects (e.g., major weight gain, cardiovascular effects, etc.). The side effect profile of current antipsychotics further decreases compliance in a patient population that is already frequently non-compliant. Thus, there exists a clear need for new therapeutics to treat schizophrenia and related disorders (e.g., schizoaffective disorder).
Clozapine is an example of an antipsychotic that has major side effects, including sialorrhea (hypersalivation) which occurs in up to 54% of patients. (Davydov and Botts, Ann Pharmacother. 34:662. 2000). The exact mechanism of hypersalivation remains unknown. (Rogers and Shramko. Pharmacotherapy. 20:109. 2000). Clozapine has a complex pharmacological profile with appreciable activity at a variety of receptors, including dopamine receptors, serotonin receptors, adrenergic receptors, muscarinic receptors and possibly others. (Coward. Br J Psychiatry Suppl. 17:5. 1992). Investigators have tried a variety of pharmacological approaches in an attempt to counteract sialorrhea, including botulinum toxin (Kahl et al. Nervenarzt. 76:205. 2005) as well as the antipsychotics amisulpride (Croissant et al. Pharmacopsychiatry. 38:38. 2005) and sulpiride. (Kreinin et al. Isr J Psychiatry Relat Sci. 42:61. 2005). Efforts have focused mostly on alpha2 adrenergic agonists as well as anti-cholinergic drugs due to clozapine's known interaction with these receptors. Anti-muscarinic drugs such as pirenzepine have shown efficacy in small scale trials (Schneider et al. Pharmacopsychiatry. 37:43. 2004), but other trials with the same agent found no effect. (Bai et al. J Clin Psychopharmacol. 21:608. 2001). Alpha2 adrenergic agonist such as clonidine (Singh et al., J Psychopharmacol. 19:426. 2005) have also shown efficacy in reducing sialorrhea in small scale trials. However, Syed et al. reported in a 2008 review that there is inadequate data to guide clinical practice. (Syed et al. Cochrane Database Syst Rev. 16:3. 2008).
Another approach to the treatment of schizophrenia has been use of muscarinic agonists. Muscarinic receptors are G-protein linked receptors that bind the neurotransmitter acetylcholine. (Eglen R M. Auton Autacoid Pharmacol 26: 219. 2006). To date, five subtypes of muscarinic receptor have been identified and are generally labeled M1, M2, M3, M4, and M5, respectively. (Caulfield M P et al. Pharmacol. Rev. 50: 279. 1998). These muscarinic subtypes vary in terms of the affinity of various agonists and antagonists for the receptors. A number of lines of evidence have suggested that the muscarinic system plays a significant role in the pathology of schizophrenia. In particular, decreased expression of M1 and M4 receptor subtypes has been noted in post-mortem studies in deceased schizophrenic patients. (Dean et al. Mol Psych. 1: 54. 1996). Likewise, SPECT imaging studies have shown decreased muscarinic availability in schizophrenia. (Raedler et al. Am J Psych.160:118. 2003).
There is also pharmacological evidence implicating activation of muscarinic receptors as a potential therapeutic approach to schizophrenia. For example, the muscarinic antagonist scopolamine, which is used to treat motion sickness, produces cognitive impairment and delusions of the type seen in schizophrenia. (Ellis et al. Int. J. Neuropsychopharmacol. 9:175. 2006). More selective M1 agonists have been suggested to potentiate glutamate signaling which could help exert a therapeutic effect. (Jones et al. J. Neurosci. 28:10422. 2008). In a double-blind placebo controlled trial of schizophrenic patients using xanomeline, which has preferential activity at the M1 and M4 receptors, alleviation of schizophrenia was observed. (Shekhar et al. Am. J. Psych. 165: 1033. 2008). However, because xanomeline also bound to subtypes of receptors other than M1, a number of various serious side effects were observed including GI side effects, cardiac side effects and problems with hyper-salivation.
During the development of xanomeline, dose-limited adverse events were problematic and led to very high discontinuation rates (including a 56% dropout rate in a 26-week study of Alzheimer's disease) and eventually to discontinuation of xanomeline development. Despite the earlier promise of targeting muscarinic acetylcholine receptors for the treatment of CNS disorders as demonstrated in part by the clinical efficacy signal observed with xanomeline, no active pharmaceutical industry development for xanomeline has occurred for more than 15 years due to adverse events observed in previous studies. Many companies have attempted to develop muscarinic acetylcholine agonists for CNS disorders as is reflected in the collection of muscarinic activators disclosed herein, but no such agonist has reached the market, due to problematic tolerability profiles. The focus of these past development efforts has been an attempt to use medicinal chemistry to develop a molecule that would be more tolerable, typically by attempting to gain selectivity for the M1 and M4 muscarinic receptors subtypes over the M2 and M3 subtypes. The M2 and M3 subtypes are believed to be the main cause of the problematic adverse events with muscarinic activators, although M1 and M4 may play a role as well.
There is a need in the art to improve the tolerability of xanomeline, which could permit the development of xanomeline as a potential first-in-class, novel-mechanism-of-action agent for the treatment of cognitive and psychotic symptoms across a number of disorders for which there is a significant medical need, including schizophrenia, Alzheimer's disease, and others. In schizophrenia, existing treatments rely upon activity at the dopamine and serotonin receptors, as was the case with the first antipsychotic, chlorpromazine, which was discovered in 1952. For more than 60 years, the same fundamental pharmacology has provided the standard of care in schizophrenia. Current antipsychotics only have efficacy for positive symptoms while leaving negative and cognitive symptoms untreated. The lack of novel treatments over the last 60 years demonstrates the difficulty in developing new medicine in schizophrenia. Alzheimer's disease is another therapeutic area in which it has proven extremely difficult to develop new therapies, with a reported success rate for molecules that enter clinical development being approved by regulatory agencies for use of only 0.4% (Cummings et al., Alzheimers Res. Ther. 2014 Jul. 3; 6(4):37). New treatments are desperately needed by patients in these areas, but development has proved extremely difficult despite substantial effort from scientist and drug developers around the world.
To date, no one has been able to harness the approach of employing muscarinic agonists because of the side effects associated with the agents' binding certain muscarinic receptor subtypes. A need exists for a method of using muscarinic agonists and for a medicament employing such muscarinic agonists that would allow for the therapeutic effects associated with activation of muscarinic receptors, but with fewer side effects.